Cost‐effectiveness of prophylactic emicizumab versus prophylactic recombinant factor VIII in patients with moderate or mild hemophilia A without inhibitors in the United States
Authors: Kunal C. Potnis, Giri Viswanathan, Robert D. Bona, Satoko Ito, Christine L. Kempton, Ankur Pandya, Harlan M. Krumholz, George Goshua
Journal: American Journal of Hematology (2023)

Prophylactic emicizumab is cost-ineffective in adults with moderate or mild hemophilia A without inhibitors at current pricing. The price of prophylactic emicizumab would need to decrease by >35% to become cost-effective in this patient population. Emicizumab (Roche, Basel, Switzerland) is a novel, bispecific monoclonal antibody that mimics activated factor VIII (FVIII).1 Unlike intravenous treatment options, emicizumab is delivered via routine subcutaneous injection, allowing for less frequent and more convenient administration.2 In the HAVEN 6 trial, patients with non-severe hemophilia A without inhibitors on prophylactic emicizumab had an estimated 67% decrease in treated bleeding monthly probability relative to the 24 weeks before study initiation on prophylactic recombinant FVIII.3 While demonstrating promising efficacy, emicizumab carries a high price tag with maintenance dosing costing approximately $47 000 per month in the United States, regardless of therapeutic indication.4 The cost-effectiveness of emicizumab in patients with non-severe hemophilia A without inhibitors is not currently known. To fill this gap, we sought to examine the cost-effectiveness of prophylactic emicizumab compared with prophylactic standard recombinant FVIII in adults with moderate or mild hemophilia A without inhibitors in the United States. Methodologically, we developed a Markov model to evaluate the quality-adjusted life expectancy and costs for these patients. We used a lifetime time horizon with a 1-month Markov cycle, an annual discount rate of 3% for cost and health outcomes, and a United States' payer perspective at a willingness-to-pay threshold (WTP) of $150 000 per quality-adjusted life year (QALY). We constructed our model to reflect the patients with moderate or mild hemophilia A without inhibitors enrolled in the HAVEN 6 trial.3 Individuals were assigned to one of two treatment arms: emicizumab prophylaxis or standard recombinant FVIII prophylaxis (“standard of care”). Within each arm, our Markov model comprised five disease states (Figure 1). Patients entered the model in a start state without bleeding events and without long-term joint damage, with joint damage accruing over time. From this state, patients could experience no new bleeding event (remain in “no bleed” state), a new treated bleeding event without hemarthrosis, a new treated bleeding event that is hemarthrosis, joint replacement surgery for accrued long-term joint damage, or death. With each bleeding event, patients receive treatment as recommended in the World Federation of Hemophilia guidelines.5 After spending a cycle in one of these states, patients return to the “no bleed” state, in which they are exposed to the same risks again. Patients could move to the death state at any point, based upon sex- and age-dependent US background mortality. The primary outcome of our analysis was the incremental cost-effectiveness ratio (ICER) for the use of prophylactic emicizumab compared with prophylactic standard recombinant FVIII. The two secondary outcomes were threshold analyses for the (1) chronic arthropathy reduction with prophylactic emicizumab use and (2) price of emicizumab that would make prophylactic emicizumab cost-effective. Transition probabilities, costs, and utilities informing our model are in Supplementary Table 1. Deterministic sensitivity and three scenario analyses are reported in the Supplement. Patients who received emicizumab prophylaxis in our model experienced 62% less treated bleed events over their lifetime than patients who received recombinant FVIII prophylaxis. Similarly, patients on emicizumab experienced 64% less hemarthrosis events compared with those who received standard of care prophylaxis. The emicizumab strategy accrued 18.9 discounted QALYs at a discounted cost of $17 400 000, and the standard-of-care strategy accrued 18.5 discounted QALYs at a discounted cost of $11 600 000. Together, this resulted in an ICER of 14.5 million USD/QALY (95% credible interval: $8 530 000/QALY–$28 400 000/QALY) for prophylactic emicizumab compared to standard of care (Figure 1; Supplementary Table 2). In probabilistic sensitivity analysis, prophylaxis with standard recombinant FVIII was favored in 100% of 10 000 Monte Carlo iterations (Figure 1). The two secondary outcome threshold analyses demonstrated that (1) a 100% reduction in the prevalence of chronic arthropathy (i.e., 0% chronic arthropathy) decreased the ICER to $1 160 000/QALY and (2) the cost of 1 mg of emicizumab would need to decrease by approximately 35% to $64.60 in order to be cost-effective at a WTP of $150 000/QALY. While displaying a clear clinical benefit in trials including HAVEN 6, bispecific antibody agents, such as emicizumab, are costly per dose and administered indefinitely, warranting careful population-level consideration of their value. In this study, we found prophylactic emicizumab to be cost-ineffective compared with standard of care in patients with non-severe hemophilia A without inhibitors in the United States, a finding robustly corroborated by deterministic and probabilistic sensitivity analyses as well as scenario analyses. Our results highlight the need for greater attention to indication-based pricing of novel therapies, such as emicizumab, where alternate pricing mechanisms may play a role in achieving cost-effectiveness.6 This study extends the literature in several ways. To our knowledge, this is the first study to examine the cost-effectiveness of prophylactic emicizumab compared to standard of care in patients with moderate or mild hemophilia A without inhibitors. Prior studies have analyzed the cost-effectiveness of prophylactic emicizumab in the context of patients with severe hemophilia A. In a study by Yu and colleagues, emicizumab prophylaxis was found to be cost-saving in Canada among patients with severe hemophilia A, dominating the standard of care prophylaxis strategy.7 In reports by the Institute for Clinical and Economic Review, emicizumab prophylaxis was found to be cost-saving in the United States among patients with severe hemophilia A without inhibitors as well as among patients with hemophilia A with inhibitors.8, 9 It is worth noting that the baseline prevalence of bleeding events and other hemophilia A-related complications is known to be less in the moderate or mild population than in the severe population. This lower baseline, without a decreased price of prophylactic emicizumab that reflects the actualized clinical benefit, contributes to the cost-ineffectiveness of emicizumab for patients with moderate or mild hemophilia A—a stark discordance from its cost-saving nature in patients with severe hemophilia A.10 Our analysis has several strengths. First, we base our clinical parameters for both arms off the latest phase 3 data for the moderate or mild hemophilia A without inhibitor population. Second, our dosages for prophylactic and on-demand recombinant FVIII are derived from the most recent World Federation of Hemophilia guidelines.5 Third, we base our cost figures off of data from Medicare, the largest payer for healthcare in the United States. Fourth, we assess the potential effect of emicizumab prophylaxis on reduction in lifetime chronic arthropathy, noting that even a reduction to 0% chronic arthropathy with emicizumab prophylaxis cannot make it cost-effective at current pricing. Fifth, we show our conclusion holds in all scenario analyses, inclusive of extended half-life recombinant FVIII (Supplement). Our model also has limitations. First, utility data were not collected in the HAVEN 6 trial, which prompted us to draw on previously published utility data for patients with moderate hemophilia A.11 We addressed this in sensitivity analyses. Second, there is an uncapturable component of a secular trend in the absence of randomization given the HAVEN 6 before-after phase 3 trial design. Given that each patient effectively serves as their own control along with the study time frame, any secular trend should have a minimal effect on bleed rates, which we also addressed in sensitivity analyses. Third, in this analysis, we took a United States' payer perspective, and analyses in other health systems will be necessary to determine the cost-effectiveness of prophylactic emicizumab around the world. Fourth, without available data on the disutility of three-times weekly intravenous administration of standard recombinant FVIII avoided with emicizumab use, our analysis does not account for this disutility. This would contribute to a lower ICER for emicizumab, although this alone is unlikely to bring the ICER from 14.5 million USD/QALY to below a WTP of $150 000/QALY. Fifth, the sample size of the HAVEN 6 trial is limited to 72 patients with a follow-up period of 55 weeks; however, this trial is still the largest to date examining prophylactic emicizumab use in patients with moderate or mild hemophilia A without inhibitors. Sixth, the patients with mild disease in the HAVEN 6 trial overall had a “more severe” mild phenotype with a median endogenous FVIII activity level of 0.0642 UI/mL, closer to moderate disease. This would suggest prophylactic emicizumab would be even more cost-ineffective in patients with “less severe” mild hemophilia A. In conclusion, at current pricing, prophylactic emicizumab was found to be a cost-ineffective strategy in patients with moderate or mild hemophilia A without inhibitors over a lifetime time horizon in the United States. This conclusion holds even if prophylactic emicizumab were to decrease chronic hemophilic arthropathy to 0%. Indication-based pricing across existing expensive medications, such as emicizumab for patients with moderate or mild hemophilia A without inhibitors, would aid the goal of a value-based care transformation of the United States' health system—that is, improving patient outcomes at costs commensurate with clinical improvement.12 Kunal C. Potnis and George Goshua had full access to all of the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. Kunal C. Potnis, Christine L. Kempton, and George Goshua are responsible for the concept and design of the study. Kunal C. Potnis and George Goshua are responsible for the acquisition, analysis, and interpretation of the data. Kunal C. Potnis, Giri Viswanathan, and George Goshua drafted the initial manuscript. Kunal C. Potnis, Giri Viswanathan, Robert D. Bona, Satoko Ito, Christine L. Kempton, Ankur Pandya, Harlan M. Krumholz, and George Goshua critically revised the manuscript for important intellectual content. This work was supported by the Bunker Endowment (G.G.). Christine L. Kempton received honoraria for advisory board participation with Genetech, Biomarin, Spark Therapeutics, and Pfizer. In the past 3 years, Harlan M. Krumholz has received expenses and/or personal fees from UnitedHealth, Element Science, Eyedentifeye, and F-Prime. He is a co-founder of Refactor Health and HugoHealth and is associated with contracts, through Yale New Haven Hospital, from the Centers for Medicare & Medicaid Services, and through Yale University, from the Food and Drug Administration, Johnson & Johnson, Google, and Pfizer. The remaining authors declare no competing financial interests. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Supporting information. 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